The mechanisms by which general anesthetics and analgesics have their clinically desired effects are not understood. The work proposed in this Program seeks to define the molecular target(s) for these drugs, and to clarify the way in which action at these targets results in anesthesia or analgesia. The underlying idea is that these drugs act on proteins, and in particular on membrane channels involved in information transfer between neurons at synapses. The available data indicate that anesthetics and analgesics can affect a number of membrane channels (both voltage- and ligand-gated), and that some of the changes could underlie a decrease in excitability of nerve cells. Unfortunately, there are few quantitative data which allow determination of the specificity of effects, or assessment of the likelihood that a given effect might be related to production of the clinically desired results. One goal of the Program is to determine likely neuronal targets of anesthetics and analgesics, by quantitatively examining the dose-effect relationship of drug action on membrane currents in neurons. One project will study effects on voltage-gated calcium- selective channels (Drs. Lingle ), which are of central importance in activity-dependent transmitter release and neuronal excitability. Two projects will study drug actions on postsynaptic transmitter-gated channels (Drs. Covey and Steinbach), which are essential to the response of the postsynaptic cell. Comparing and contrasting the results of these studies will indicate channels whose function is altered by clinically relevant concentrations of drug, and will determine which actions are characteristic of anesthetics or analgesics. A final goal of the Program is to elucidate the mechanism by which anesthetics and analgesics have their effects on proteins, by analyses of pharmacological and kinetic data obtained in the projects. The results obtained will provide information required to determine likely cellular and molecular actions which underlie the clinically desired effects of these drugs. Furthermore, insights will be gained into the mechanisms by which anesthetics and analgesics have their actions.